Project 2: Radiation Biodosimetry using Gene Expression Signatures. Gene expression represents a practical approach to biodosimetry, but studies have generally focused only on acute external photon exposure. Differential gene expression responses may result from other types of exposures important for radiological triage, and much work will still be required to refine signatures for gene expression-based biodosimetric assays for application in situations where the radiation exposure is complex. The proposed studies will characterize contributions of dose rate, the internal emitter 137Cs, and the neutron component of improvised nuclear device (IND) radiation to gene expression responses relevant to radiation biodosimetry. Furthermore, dose estimates provide only a general idea of the average radiation injury expected across a population, with predictors of individual radiation injury response and outcome potentially being even more useful. Blood-based transcriptomic predictors for individualized risk of death from radiation-induced lung injury will be developed, as well as gene expression signatures of lung injury and recovery. Inflammatory processes are activated by radiation exposure and are important contributors to late disease. Chronic inflammatory conditions or immunosuppression also have the potential to confound radiation biodosimetric signatures in individuals, so investigation of the impact of inflammatory pathways on biodosimetric signatures will be initiated using mouse models. All the proposed research is ultimately directed toward developing practical biodosimetry solutions for emergency radiological triage. In support of this larger goal, an integrated blood collection device compatible with self-administration will be tested in collaboration with the Sample Engineering Core for its ability to deliver high quality samples for quantification of mRNA levels by downstream measurement methods. This will begin to address sample collection, a key neglected bottleneck for implementation of gene expression-based radiation biodosimetry. The gene expression profiling studies proposed in this project will be complemented by investigations of cytogenetic endpoints (Project 1) and metabolomic profiling (Project 3) leveraging shared biological samples and experimental designs. The Cores will further enhance the planned research by centralizing and standardizing routine functions, such as mouse handling and irradiations, and by providing unique resources, such as the IND-spectrum neutron source and the variable dose rate external 137Cs irradiator (Irradiation Core), and the hematopoietically humanized mouse for biodosimetry (Mouse Core).